Reversible and irreversible acetylcholinesterase inhibitors cause changes in neuronal amyloid precursor protein processing and protein kinase C levelin vitro

The alternative routes of cleavage of the amyloid precursor protein (APP) r esult in the generation and secretion of both soluble APP and beta -amyloid , the latter being the main component of the amyloid deposits in the brains of individuals with Alzheimer's disease (AD). This study examined the ques tion of whether acetylcholinesterase (AChE) inhibitors can alter the proces sing of APP and the level of protein kinase C (PKC) in primary rat basal fo rebrain cultures. Western blotting was used to test two AChE inhibitors (re versible and irreversible) for their ability to enhance the release of APP and PKC content. These inhibitors were ambenonium (AMB) and metrifonate (MT F), at different concentrations. A significant increase was found in the ce ll-associated APP level in a basal forebrain neuronal culture, and there wa s an elevation of the APP release into the medium. Increases were similarly observed in the PKC levels after AMB or MTF treatment. The results suggest that these AChE inhibitors promote the non-amyloidogenic route of APP proc essing, which may be due to their stimulatory effects on PKC. The PKC activ ation may enhance the alpha -secrctase activity and consequently the produc tion of the N-terminal APP. Since both a decreased level of APP secretion a nd a low activity and level of PKC may be involved in the pathogenesis of A D, it is concluded that the administration of AChE inhibitors to AD patient s may facilitate the memory processes and exert a neuroprotective effect. ( C) 2001 Elsevier Science Ltd. All rights reserved.